WO1997009310A1 - 1-phenyl-3-4-[benzylpiperidinyl-1]-propanol-1 derivatives, preparation thereof and therapeutical application thereof - Google Patents

1-phenyl-3-4-[benzylpiperidinyl-1]-propanol-1 derivatives, preparation thereof and therapeutical application thereof Download PDF

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Publication number
WO1997009310A1
WO1997009310A1 PCT/FR1996/001361 FR9601361W WO9709310A1 WO 1997009310 A1 WO1997009310 A1 WO 1997009310A1 FR 9601361 W FR9601361 W FR 9601361W WO 9709310 A1 WO9709310 A1 WO 9709310A1
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Prior art keywords
general formula
methyl
ketone
hydrochloride
phenylmethyl
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PCT/FR1996/001361
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French (fr)
Inventor
Jonathan Frost
Bernard Gaudilliere
Jean Rousseau
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Synthelabo
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Priority to AU69343/96A priority Critical patent/AU6934396A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Definitions

  • R ⁇ represents a hydrogen or halogen atom or a methyl or methoxy group
  • R 2 represents a hydrogen atom or a methyl group
  • R 3 represents a hydrogen or halogen atom.
  • R 2 represents hydrogen
  • the compounds of general formula (I) have in their molecule an asymmetric carbon atom; they can therefore be in the form of two enantiomers.
  • R 2 represents a methyl group
  • the compounds of general formula (I) have in their molecule two contiguous asymmetric carbon atoms; they can therefore be presented in two diastereoisomeric forms, erythro and threo, each of which comprises two enantiomers.
  • the base is released from 10 g of the hydrochloride prepared previously and to the oil thus obtained, 100 ml of ethanol, 10 ml of water, 1 g of soda and then 10 g of potassium borohydride are added, and the mixture is stirred at room temperature for 7 h.
  • the product is purified by chromatography on an aluminum column, eluting with a 90/10 mixture of toluene and chloroform.
  • the hydrochloride is prepared from it in a mixture of diethyl ether and hydrochloric acid, and it is recrystallized from ethanol. Melting point: 215-216 ° C.
  • the hydrochloride is prepared as indicated above with respect to the other diastereoisomer. Melting point: 182-184 ° C.
  • the compounds of the invention have been the subject of tests which have demonstrated their interest as therapeutic substances.
  • mice were subjected to the test of global cerebral ischemia in mice.
  • the ischemia is due to cardiac arrest induced by a rapid intravenous injection of magnesium chloride.
  • the "survival time” is measured, that is to say the interval between the moment of injection of magnesium chloride and the last observable respiratory movement of each mouse. This last movement is considered the ultimate index of a function of the central nervous system. Respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride.
  • mice Male mice (Charles River CD1) are studied in groups of 10. They are fed and watered ad libitum before the tests. The survival time is measured 10 minutes after the intraperitoneal administration of the compounds of the invention. The results are given in the form of the difference between the survival time measured in a group of 10 mice having received the compound and the survival time measured in a group of 10 mice having received the vehicle liquid. The relationships between the modifications in the survival term and the dose of the compound are recorded graphically according to a semilogarithmic curve.
  • This curve allows the calculation of the "effective dose 3 seconds" (DE 3 ⁇ ), that is to say the dose (in mg / kg) which produces a 3 second increase in survival time compared to the control group of 10 untreated mice.
  • a 3 second increase in survival time is both statistically significant and reproducible.
  • the ED 3 "of the most active compounds are less than 20 mg / kg intraperitoneally.
  • the compounds of the invention have also been the subject of a test for inhibition of the binding of [ 3 H] ifenprodil in the rat cerebral cortex (Schoemaker et al., Eur. J. Phar ⁇ macol. (1990 ) 183 1670).
  • Ultra-Turrax TM Ikawerk
  • Polytron TM Polytron TM
  • the homogenate is washed twice by centrifugation for 10 minutes at 45,000 ⁇ g, the pellet being resuspended in fresh buffer.
  • the final pellet is taken up in 20 volumes of the same buffer.
  • a 100 ⁇ l aliquot of this suspension is incubated in a final volume of 1000 ⁇ l with 0.5 nM of [ 3 H] ifenprodil (specific activity: 30 to 35 Ci / mmol) for 30 minutes at 37 ° C., in the absence or presence of a competing substance.
  • the membranes are recovered by filtration on Whatman GF / B TM filters pretreated with 0.05% polyethyleneimine, then washed with twice 5 ml of ice-cold buffer.
  • the non-specific binding is determined with lO ⁇ M ifenprodil, the data are analyzed according to the usual methods, and the IC 50 concentration is calculated, a concentration which inhibits the binding of [ 3 H] ifenprodil by 50%.
  • the IC 50 values of the most active compounds are less than 50 nM.
  • cerebral disorders such as those which are consecutive, for example, to an ischemic attack, a cardiac or respiratory arrest, a thrombosis or a cerebral embolism, for the treatment of cerebral senility, dementia following multiple infarctions, senile dementia, for example Alzheimer's disease or Pick's disease, for the treatment of olivoponto-cerebellar atrophy and other neurodegenerative diseases such as Huntington's chorea, amyotrophic lateral sclerosis, for the treatment of cranial or spinal trauma, for the prevention of weak neuronal damage health following convulsive states or the presence of tumors in the nervous system, for the treatment of neurological alterations due to AIDS, for the prevention and treatment of diabetic retinopathies, degeneration of the optic nerve and retinopathies associated with glaucoma.
  • cerebral disorders such as those which are consecutive, for example, to an ischemic attack, a cardiac or respiratory arrest, a thrombosis or a cerebral embolism
  • cerebral senility dementia following
  • peripheral neuropathies such as traumatic neuropathies (section or crushing of a nerve) or ischemic neuropathies, metabolic neuropathies (diabetes, uremia), infectious, alcoholic and medicinal neuropathies, neuropathies genetics, motor neuron conditions such as spinal muscular atrophies and amyotrophic lateral sclerosis.
  • the compounds of the invention can also be used in combination with thrombolytic agents such as rt-PA (tissue activator of recombinant plasminogen, of human origin) for the treatment of cerebral infarctions of the thromboenbolic type, or in combination with a compound reducing intraocular pressure for the treatment of glaucoma, or alternatively in combination with an anticancer agent, with a view to reducing the side effects (neuropathies, etc.) of the latter.
  • thrombolytic agents such as rt-PA (tissue activator of recombinant plasminogen, of human origin) for the treatment of cerebral infarctions of the thromboenbolic type
  • rt-PA tissue activator of recombinant plasminogen, of human origin
  • a compound reducing intraocular pressure for the treatment of glaucoma
  • an anticancer agent with a view to reducing the side effects (neuropathies, etc.) of the latter.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Compounds of general formula (I), wherein R1 is a hydrogen or halogen atom or a methyl or methoxy group, R2 is a hydrogen atom or a methyl group, and R3 is a hydrogen or halogen atom, are useful for therapeutical applications.

Description

DERIVES DE l-PHENYL-3-[4-BENZYLPIPERIDINYL-l]-PR0PAN0L-l , LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUEL-PHENYL-3- [4-BENZYLPIPERIDINYL-l] -PR0PAN0L-l DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
Les composés de l ' invention répondent à la formule générale ( I )The compounds of the invention correspond to the general formula (I)
Figure imgf000003_0001
dans laquelle
Figure imgf000003_0001
in which
Rλ représente un atome d'hydrogène ou d'halogène ou un groupe méthyle ou méthoxy, R2 représente un atome d'hydrogène ou un groupe méthyle, et R3 représente un atome d'hydrogène ou d'halogène.R λ represents a hydrogen or halogen atom or a methyl or methoxy group, R 2 represents a hydrogen atom or a methyl group, and R 3 represents a hydrogen or halogen atom.
Lorsque R2 représente l'hydrogène, les composés de formule générale (I) comportent dans leur molécule un atome de carbone asymétrique ; ils peuvent donc se présenter sous la forme de deux énantiomères.When R 2 represents hydrogen, the compounds of general formula (I) have in their molecule an asymmetric carbon atom; they can therefore be in the form of two enantiomers.
Lorsque R2 représente un groupe méthyle, les composés de formule générale (I) comportent dans leur molécule deux atomes de carbone asymétriques contigus ; ils peuvent donc se présenter sous deux formes diastéréoisomères, érythro et thréo, dont chacune comprend deux énantiomères.When R 2 represents a methyl group, the compounds of general formula (I) have in their molecule two contiguous asymmetric carbon atoms; they can therefore be presented in two diastereoisomeric forms, erythro and threo, each of which comprises two enantiomers.
Ces diverses formes d'isomères optiques font partie de 1 'invention.These various forms of optical isomers are part of the invention.
Font également partie de l'invention les sels d'addition que peuvent former les composés de formule générale (I) avec des acides .The addition salts which the compounds of general formula (I) can form with acids are also part of the invention.
Les composés de l'invention peuvent être préparés par des procédés illustrés par les schémas qui suivent. Schéma 1The compounds of the invention can be prepared by methods illustrated by the schemes which follow. Diagram 1
^^
Figure imgf000004_0001
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0002
Selon le schéma 1, on fait réagir une cétone de formule générale (II), dans laquelle R2 et R2 sont tels que définis ci-dessus, avec une 4- (phenylmethyl) pipéridine de formule générale (III) , dans laquelle R3 est tel que défini ci- dessus, en présence de paraformaldéhyde et en milieu acide, à la température de reflux d'un solvant tel que l'éthanol. Finalement on réduit la cétone de formule générale (IV) , ainsi obtenue, par hydrogénation catalytique ou bien, et de préférence, par action d'un borohydrure de métal alcalin. Schéma 2According to scheme 1, a ketone of general formula (II), in which R 2 and R 2 are as defined above, is reacted with a 4- (phenylmethyl) piperidine of general formula (III), in which R 3 is as defined above, in the presence of paraformaldehyde and in an acidic medium, at the reflux temperature of a solvent such as ethanol. Finally, the ketone of general formula (IV), thus obtained, is reduced by catalytic hydrogenation or, and preferably, by the action of an alkali metal borohydride. Diagram 2
Figure imgf000005_0001
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000005_0002
Selon le schéma 2, on fait réagir une cétone bromée de formule générale (V) , dans laquelle R± et R2 sont tels que définis ci-dessus, avec une 4- (phenylmethyl) pipéridine de formule générale (III), dans laquelle R3 est tel que défini ci-dessus, er: présence d'une base et dans un solvant tel que 1'acétonitrile, à une température de 20 à 90°C. Finalement on réduit la cétone de formule générale (IV), ainsi obtenue, par action d'un borohydrure de métal alcalin.According to scheme 2, a brominated ketone of general formula (V), in which R ± and R 2 are as defined above, is reacted with a 4- (phenylmethyl) piperidine of general formula (III), in which R 3 is as defined above, er: presence of a base and in a solvent such as acetonitrile, at a temperature of 20 to 90 ° C. Finally, the ketone of general formula (IV) thus obtained is reduced by the action of an alkali metal borohydride.
Les produits de départ sont connus, décrits dans la littéra¬ ture ou directement disponibles dans le commerce. Les exemples suivants illustrent en détail la préparation de quelques composés selon l'invention. Les microanalyses élé¬ mentaires et les spectres IR et RMN confirment les struc¬ tures des composés obtenus. Les numéros des composés indiqués entre parenthèses dans les titres correspondent à ceux du tableau donné plus loin.The starting materials are known, described in the literature or directly available commercially. The following examples illustrate in detail the preparation of some compounds according to the invention. The elementary microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained. The numbers of the compounds indicated in parentheses in the titles correspond to those of the table given below.
Exemple 1 (Composé N°l)Example 1 (Compound No. 1)
(±) -érythro β-méthyl-α-phényl-4- (phenylmethyl) pipéridine- 1-propanol, chlorhydrate.(±) -erythro β-methyl-α-phenyl-4- (phenylmethyl) piperidine- 1-propanol, hydrochloride.
1.1. 2-Méthyl-l-phényl-3- [4- (phenylmethyl)pipéridin-1-yl] - propanone, chlorhydrate.1.1. 2-Methyl-1-phenyl-3- [4- (phenylmethyl) piperidin-1-yl] - propanone, hydrochloride.
On introduit dans un ballon 13,4 g de 1-phénylpropanone, 19,25 g de 4- (phenylmethyl) pipéridine, 3,3 g de paraform- aldéhyde, 20 ml d'ethanol et 1 ml d'acide chlorhydrique concentré, et on chauffe le mélange au reflux pendant 16h.13.4 g of 1-phenylpropanone, 19.25 g of 4- (phenylmethyl) piperidine, 3.3 g of paraform-aldehyde, 20 ml of ethanol and 1 ml of concentrated hydrochloric acid are introduced into a flask. the mixture is heated at reflux for 16 h.
On évapore l'éthanol sous pression réduite, on ajoute au résidu 250 ml d'éther diéthylique et 20 ml d'éther chlor- hydrique, et on recristallise le précipité obtenu dans l'éthanol. On obtient 10,7 g de composé.The ethanol is evaporated off under reduced pressure, 250 ml of diethyl ether and 20 ml of hydrochloric ether are added to the residue, and the precipitate obtained is recrystallized from ethanol. 10.7 g of compound are obtained.
Point de fusion : 174-175°C.Melting point: 174-175 ° C.
1.2. ( ± ) - érythro β-méthyl-α-phényl-4- (phenylmethyl) pipéri- dine-1-propanol, chlorhydrate.1.2. (±) - erythro β-methyl-α-phenyl-4- (phenylmethyl) piperidin-1-propanol, hydrochloride.
On libère la base de 10 g du chlorhydrate préparé précé¬ demment et, à l'huile ainsi obtenue, on ajoute 100 ml d'ethanol, 10 ml d'eau, 1 g de soude puis 10 g de boro¬ hydrure de potassium, et on agite le mélange à température ambiante pendant 7h.The base is released from 10 g of the hydrochloride prepared previously and to the oil thus obtained, 100 ml of ethanol, 10 ml of water, 1 g of soda and then 10 g of potassium borohydride are added, and the mixture is stirred at room temperature for 7 h.
On ajoute 100 ml d'eau et on laisse au repos pendant une nuit.100 ml of water are added and the mixture is left to stand overnight.
On ajoute encore 100 ml d'eau et on extrait avec trois foisAnother 100 ml of water are added and the mixture is extracted with three times
150 ml d'acétate d'éthyle, on sèche et évapore la phase organique, et on sépare les formes érythro et thréo par chromatographie sur alumine en éluant avec un mélange 90/10 de toluène et de chloroforme.150 ml of ethyl acetate, the organic phase is dried and evaporated, and the erythro and threo forms are separated by chromatography on alumina, eluting with a 90/10 mixture of toluene and chloroform.
On reprend le diastéréoisomère érythro pur (Rf inférieur) avec de l'éther chlorhydrique et on recristallise le préci- pité blanc obtenu dans de l'éthanol aqueux (1/1) . On obtientThe pure erythro diastereoisomer (lower Rf) is taken up with hydrochloric ether and the precursor is recrystallized. white pity obtained in aqueous ethanol (1/1). We obtain
1,28 g de composé.1.28 g of compound.
Point de fusion : 199-200°C.Melting point: 199-200 ° C.
Exemple 2 (Composé N°2)Example 2 (Compound # 2)
(±) - thréo β-méthyl-α-phényl-4- (phenylmethyl) pipéridine- 1-propanol, chlorhydrate.(±) - threo β-methyl-α-phenyl-4- (phenylmethyl) piperidine- 1-propanol, hydrochloride.
On reprend le diastéréoisomère thréo pur (Rf supérieur) , séparé prededemment, avec de l'éther chlorhydrique et on recristallise le précipité blanc obtenu dans de l'acétone. On obtient 1,03 g de composé. Point de fusion : 149-150°C.The pure threo diastereoisomer (higher Rf), separated previously, is taken up with hydrochloric ether and the white precipitate obtained is recrystallized from acetone. 1.03 g of compound are obtained. Melting point: 149-150 ° C.
Exemple 3 (Composé N°4)Example 3 (Compound # 4)
(±) -érythro α- (4-Chlorophényl) -β-méthyl-4- (phenylmethyl) - pipéridine-1-propanol, chlorhydrate.(±) -erythro α- (4-Chlorophenyl) -β-methyl-4- (phenylmethyl) - piperidine-1-propanol, hydrochloride.
3.1. 1- (4-Chlorophényl) -2-méthyl-3- [4- (phenylmethyl) pipé- ridin-l-yl]propanone, chlorhydrate.3.1. 1- (4-Chlorophenyl) -2-methyl-3- [4- (phenylmethyl) piperidin-1-yl] propanone, hydrochloride.
On introduit dans un ballon 16,8 g de 1- (4-chlorophényl)pro- panone, 19,25 g de 4- (phenylmethyl) pipéridine, 3,3 g de paraformaldéhyde, 20 ml d'ethanol et 1 ml d'acide chlor¬ hydrique concentré, et on chauffe le mélange au reflux pendant 6h.16.8 g of 1- (4-chlorophenyl) propanone, 19.25 g of 4- (phenylmethyl) piperidine, 3.3 g of paraformaldehyde, 20 ml of ethanol and 1 ml of concentrated hydrochloric acid, and the mixture is heated to reflux for 6 hours.
On évapore l'éthanol sous pression réduite, on ajoute au résidu 250 ml d'éther diéthylique et 20 ml d'un mélange d'éther diéthylique et d'acide chlorhydrique, et on recris¬ tallise le précipité obtenu dans 200 ml d'ethanol. On obtient 26,23 g de composé. Point de fusion : 177-178°C.The ethanol is evaporated off under reduced pressure, 250 ml of diethyl ether and 20 ml of a mixture of diethyl ether and hydrochloric acid are added to the residue, and the precipitate obtained is recrystallized in 200 ml of ethanol . 26.23 g of compound are obtained. Melting point: 177-178 ° C.
3.2. (± ) - érythro α- (4-Chlorophényl) -β-méthyl-4- (phenyl¬ methyl)pipéridine-1-propanol, chlorhydrate. On introduit 10 g de chlorhydrate de 1- (4-chlorophényl) -3.2. (±) - erythro α- (4-Chlorophenyl) -β-methyl-4- (phenyl¬ methyl) piperidine-1-propanol, hydrochloride. 10 g of 1- (4-chlorophenyl) hydrochloride are introduced.
2-méthyl-3- [4- (phenylmethyl)pipéridin-1-yl]propanone dans un ballon, on ajoute 100 ml d'ethanol et 10 ml d'acide acétique et, sous agitation, on ajoute 10 g de borohydrure de potas¬ sium en l'espace de 30 min. Après 2h d'agitation on ajoute 100 ml d'eau et 300 ml d'acide chlorhydrique IN, et on obtient un précipité blanc qu'on collecte par filtration.2-methyl-3- [4- (phenylmethyl) piperidin-1-yl] propanone in a flask, 100 ml of ethanol and 10 ml of acetic acid are added and, with stirring, 10 g of potassium borohydride are added ¬ sium in the space of 30 min. After 2 hours of stirring, 100 ml of water and 300 ml of IN hydrochloric acid are added, and a white precipitate is obtained which is collected by filtration.
On purifie le produit par chromatographie sur colonne d'alu- mine en éluant avec un mélange 90/10 de toluène et de chlo¬ roforme.The product is purified by chromatography on an aluminum column, eluting with a 90/10 mixture of toluene and chloroform.
On en prépare le chlorhydrate dans un mélange d'éther dié¬ thylique et d'acide chlorhydrique, et on le recristallise dans l'éthanol. Point de fusion : 215-216°C.The hydrochloride is prepared from it in a mixture of diethyl ether and hydrochloric acid, and it is recrystallized from ethanol. Melting point: 215-216 ° C.
Exemple 4 (Composé N°3)Example 4 (Compound No. 3)
(±) - thréo α- (4-Chlorophényl) -β-méthyl-4- (phenylmethyl)pipé- ridine-1-propanol, chlorhydrate.(±) - threo α- (4-Chlorophenyl) -β-methyl-4- (phenylmethyl) piperidin-1-propanol, hydrochloride.
A 10 g de chlorhydrate de 1- (4-Chlorophényl) -2-méthyl- 3- [4- (phenylmethyl) pipéridin-1-yl]propanone on ajoute de l'ammoniaque à 5% pour libérer la base, et on extrait celle- ci avec de l'acétate d'éthyle. Après évaporation du solvant on ajoute au résidu 100 ml d'ethanol, 10 ml d'eau et 1 g de soude et, tout en agitant, on ajoute 9,5 g de borohydrure de potassium, on maintient l'agitation pendant 2h et on laisse reposer le mélange pendant une nuit. On évapore l'éthanol, on reprend le résidu avec 100 ml d'eau et on l'extrait trois fois avec 150 ml d'acétate d'éthyle. Après séchage de la phase organique, évaporation du solvant, purification par chromatographie sur colonne de gel de silice en éluant avec un mélange de dichlorométhane et d'acétone 90/10, on prépare le chlorhydrate de la manière déjà décrite. On obtient 1,18 g de composé. Point de fusion : 182-183°C. Exemple 5 (Composé N°9)To 10 g of 1- (4-Chlorophenyl) -2-methyl- 3- [4- (phenylmethyl) piperidin-1-yl] propanone hydrochloride is added 5% ammonia to release the base, and extracted this with ethyl acetate. After evaporation of the solvent, 100 ml of ethanol, 10 ml of water and 1 g of sodium hydroxide are added to the residue and, while stirring, 9.5 g of potassium borohydride are added, stirring is continued for 2 h and let the mixture sit overnight. The ethanol is evaporated off, the residue is taken up in 100 ml of water and extracted three times with 150 ml of ethyl acetate. After drying of the organic phase, evaporation of the solvent, purification by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and acetone 90/10, the hydrochloride is prepared in the manner already described. 1.18 g of compound are obtained. Melting point: 182-183 ° C. Example 5 (Compound # 9)
(±) -4- [ (4-Fluorophényl)méthyl] -α-phénylpipéridine-1-pro- panol, chlorhydrate.(±) -4- [(4-Fluorophenyl) methyl] -α-phenylpiperidine-1-propanol, hydrochloride.
5.1. 3- [4- [ (4-Fluorophényl)méthyl]pipéridin-l-yl]-l-phényl- propanone. On agite une suspension de 6,4 g de 3-bromo-l-phénylpro- panone (préparée selon J. Amer. Chem. Soc. (1940) 62 1435-1441), 6,9 g de chlorhydrate de 4- [ (4-fluorophényl) - méthyl]pipéridine et 16,6 g de carbonate de potassium dans 100 ml d' acétonitrile, on chauffe le mélange à 90°C, on le maintient à cette température pendant 6h et on le laisse reposer à température ambiante pendant une nuit. On sépare l'insoluble par filtration, on évapore le filtrat, on reprend le résidu avec un mélange d'éther diéthylique et d'acide chlorhydrique dilué, on sépare le solide qui se forme, on le recristallise dans l'éthanol et on le sèche.5.1. 3- [4- [(4-Fluorophenyl) methyl] piperidin-1-yl] -1-phenylpropanone. A suspension of 6.4 g of 3-bromo-1-phenylpropanone (prepared according to J. Amer. Chem. Soc. (1940) 62 1435-1441), 6.9 g of 4- [hydrochloride is stirred. 4-fluorophenyl) -methyl] piperidine and 16.6 g of potassium carbonate in 100 ml of acetonitrile, the mixture is heated to 90 ° C., it is kept at this temperature for 6 h and is allowed to stand at room temperature for a night. The insoluble material is separated by filtration, the filtrate is evaporated, the residue is taken up with a mixture of diethyl ether and dilute hydrochloric acid, the solid which forms is separated, it is recrystallized from ethanol and dried .
5.2. (±) -4- [ (4-Fluorophényl)méthyl] -α-phénylpipéridine- 1-propanol, chlorhydrate.5.2. (±) -4- [(4-Fluorophenyl) methyl] -α-phenylpiperidine- 1-propanol, hydrochloride.
On dissout 7,7 g de chlorhydrate de 3- [4- [ (4-fluorophényl) - méthyl]pipéridin-l-yl] -1-phénylpropanone dans 200 ml de méthanol, on ajoute 6, 0 g de borohydrure de potassium en l'espace de 40 min et on agite le mélange pendant 2h à température ambiante.7.7 g of 3- [4- [(4-fluorophenyl) -methyl] piperidin-1-yl] -1-phenylpropanone hydrochloride are dissolved in 200 ml of methanol, 6.0 g of potassium borohydride are added. for 40 min and the mixture is stirred for 2 h at room temperature.
On ajoute de l'eau et de l'acide chlorhydrique dilué, on agite et on évapore l'alcool sous pression réduite. On reprend le résidu pâteux avec de l'eau, on libère le base avec de l'ammoniaque et on l'extrait deux fois avec du dichlorométhane.Water and dilute hydrochloric acid are added, the mixture is stirred and the alcohol is evaporated under reduced pressure. The pasty residue is taken up with water, the base is released with ammonia and it is extracted twice with dichloromethane.
Après lavage, séchage et évaporation de la phase organique il reste une huile qui cristallise rapidement. On dissout les cristaux dans du méthanol tiède, on ajoute une solution d'acide chlorhydrique 0, IN dans du propan-2-ol, on évapore les solvants, on triture le résidu dans de l'acétone, on le sèche et on le recristallise dans du propan-2-ol. Point de fusion : 162-163°C. Exemple 6 (Composé N°13)After washing, drying and evaporation of the organic phase, an oil remains which crystallizes quickly. The crystals are dissolved in lukewarm methanol, a solution of hydrochloric acid 0, IN in propan-2-ol is added, the solvents are evaporated, the residue is triturated in acetone, it is dried and recrystallized in propan-2-ol. Melting point: 162-163 ° C. Example 6 (Compound # 13)
(±) -érythro β-Méthyl-α- (4-méthylphényl) -4- (phenylmethyl) - pipéridine-1-propanol, chlorhydrate.(±) -erythro β-Methyl-α- (4-methylphenyl) -4- (phenylmethyl) - piperidine-1-propanol, hydrochloride.
6.1. 2-Méthyl-l- (4-méthylphényl) -3- [4- (phenylmethyl)pipé- ridin-1-yl]propanone, chlorhydrate. On introduit dans un ballon 29,6 g de 1- (4-méthylphényl) - propanone, 7,83 g de paraformaldéhyde, 45,5 g de 4- (phenyl¬ methyl)pipéridine, 1 ml d'acide chlorhydrique concentré et 200 ml d'ethanol, et on chauffe le mélange au reflux pendant 8h.6.1. 2-Methyl-1- (4-methylphenyl) -3- [4- (phenylmethyl) piperidin-1-yl] propanone, hydrochloride. 29.6 g of 1- (4-methylphenyl) -propanone, 7.83 g of paraformaldehyde, 45.5 g of 4- (phenyl¬ methyl) piperidine, 1 ml of concentrated hydrochloric acid and 200 are introduced into a flask. ml of ethanol, and the mixture is heated at reflux for 8 h.
On évapore le solvant sous pression réduite, on reprend le résidu avec de l'eau acifiée avec de l'acide chlorhydrique, on extrait les produits qui n'ont pas réagi avec de l'éther diéthylique, on sépare le chlorhydrate solide par filtra¬ tion, on le lave à l'éther diéthylique, on le recristallise dans un mélange d'acétone et de propan-2-ol et on le sèche. On obtient 13 g de composé. Point de fusion : 184-186°C.The solvent is evaporated off under reduced pressure, the residue is taken up with acified water with hydrochloric acid, the products which have not reacted are extracted with diethyl ether, the solid hydrochloride is separated by filtra¬ tion, washed with diethyl ether, recrystallized from a mixture of acetone and propan-2-ol and dried. 13 g of compound are obtained. Melting point: 184-186 ° C.
6.2. {± ) -érythro β-Méthyl-α- (4-méthylphényl) -4- (phenylme¬ thyl)pipéridine-1-propanol, chlorhydrate. On libère la base de la cétone préparée précédemment, on en introduit 11 g dans un ballon de 500 ml, on ajoute 300 ml de méthanol et 11 g de borohydrure de potassium, on agite le mélange pendant 4h à température ambiante et on le laisse reposer une nuit.6.2. {±) -erythro β-Methyl-α- (4-methylphenyl) -4- (phenylme¬ thyl) piperidine-1-propanol, hydrochloride. The base of the ketone prepared above is released, 11 g of it are introduced into a 500 ml flask, 300 ml of methanol and 11 g of potassium borohydride are added, the mixture is stirred for 4 h at room temperature and left to stand a night.
On évapore le solvant sous pression réduite, on reprend le résidu avec de l'eau, on l'extrait avec de l'acétate d'éthyle, on lave la phase organique à l'eau, on la sèche et on l'évaporé.The solvent is evaporated off under reduced pressure, the residue is taken up in water, it is extracted with ethyl acetate, the organic phase is washed with water, dried and evaporated.
On sépare les formes érythro et thréo par chromatographie sur alumine en éluant avec un mélange de toluène et de chloroforme 98/2. On dissout le composé érythro dans de l'acétone, on ajoute de l'éther chlorhydrique, on sépare le précipité par filtra¬ tion, on le sèche et on le recristallise dans l'éthanol. Point de fusion : 212°C. Exemple 7 (Composé N°14)The erythro and threo forms are separated by chromatography on alumina, eluting with a mixture of toluene and 98/2 chloroform. The erythro compound is dissolved in acetone, hydrochloric ether is added, the precipitate is separated by filtration, dried and recrystallized from ethanol. Melting point: 212 ° C. Example 7 (Compound No. 14)
(±) - thréo β-Méthyl-α- (4-méthylphényl) -4- (phenylmethyl) - pipéridine-1-propanol, chlorhydrate.(±) - threo β-Methyl-α- (4-methylphenyl) -4- (phenylmethyl) - piperidine-1-propanol, hydrochloride.
On prépare le chlorhydrate comme indiqué ci-dessus à propos de l'autre diastéréoisomère. Point de fusion : 182-184°C.The hydrochloride is prepared as indicated above with respect to the other diastereoisomer. Melting point: 182-184 ° C.
Le tableau qui suit illustre les structures chimiques et les propriétés physiques de quelques composés selon l'invention.The table which follows illustrates the chemical structures and the physical properties of some compounds according to the invention.
Dans la colonne "Isomérie", " (±) " désigne un mélange racémique, "E" désigne la forme érythro et "T" désigne la forme thréo.In the "Isomerism" column, "(±)" denotes a racemic mixture, "E" denotes the erythro form and "T" denotes the threo form.
Dans la colonne "Sel", "HCl" désigne un chlorhydrate et "bnz" désigne un benzoate. In the "Salt" column, "HCl" denotes a hydrochloride and "bnz" denotes a benzoate.
TableauBoard
Figure imgf000012_0001
Figure imgf000012_0001
Les composés de l'invention ont fait l'objet d'essais qui ont mis en évidence leur intérêt comme substances thérapeu¬ tiques. The compounds of the invention have been the subject of tests which have demonstrated their interest as therapeutic substances.
Ainsi ils ont été soumis au test de l'ischémie cérébrale globale chez la souris.Thus they were subjected to the test of global cerebral ischemia in mice.
L'ischémie est due à un arrêt cardiaque induit par une injection intraveineuse rapide de chlorure de magnésium. Dans ce test on mesure le "temps de survie", c'est-à-dire l'intervalle entre le moment de l'injection de chlorure de magnésium et le dernier mouvement respiratoire observable de chaque souris. Ce dernier mouvement est considéré comme l'indice ultime d'une fonction du système nerveux central. L'arrêt respiratoire apparaît approximativement 19 secondes après l'injection de chlorure de magnésium.The ischemia is due to cardiac arrest induced by a rapid intravenous injection of magnesium chloride. In this test, the "survival time" is measured, that is to say the interval between the moment of injection of magnesium chloride and the last observable respiratory movement of each mouse. This last movement is considered the ultimate index of a function of the central nervous system. Respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride.
Des souris mâles (Charles River CD1) sont étudiées par grou¬ pes de 10. Elles sont nourries et abreuvées ad libitum avant les essais. Le temps de survie est mesuré 10 minutes après l'administration intrapéritonéale des composés de l'inven- tion. Les résultats sont donnés sous la forme de la diffé¬ rence entre le temps de survie mesuré dans un groupe de 10 souris ayant reçu le composé et le temps de survie mesuré dans un groupe de 10 souris ayant reçu le liquide véhicule. Les rapports entre les modifications dans le terme de survie et la dose du composé sont enregistrés graphiquement selon une courbe semilogarithmique.Male mice (Charles River CD1) are studied in groups of 10. They are fed and watered ad libitum before the tests. The survival time is measured 10 minutes after the intraperitoneal administration of the compounds of the invention. The results are given in the form of the difference between the survival time measured in a group of 10 mice having received the compound and the survival time measured in a group of 10 mice having received the vehicle liquid. The relationships between the modifications in the survival term and the dose of the compound are recorded graphically according to a semilogarithmic curve.
Cette courbe permet le calcul de la "dose efficace 3 secon¬ des" (DE3π), c'est-à-dire la dose (en mg/kg) qui produit une augmentation de 3 secondes du temps de survie par rapport au groupe témoin de 10 souris non traitées.This curve allows the calculation of the "effective dose 3 seconds" (DE 3 π), that is to say the dose (in mg / kg) which produces a 3 second increase in survival time compared to the control group of 10 untreated mice.
Une augmentation de 3 secondes du temps de survie est à la fois significative statistiquement et reproductible. Les DE3« des composés les plus actifs sont inférieures à 20 mg/kg par voie intrapéritonéale.A 3 second increase in survival time is both statistically significant and reproducible. The ED 3 "of the most active compounds are less than 20 mg / kg intraperitoneally.
Les composés de l'invention ont aussi fait l'objet d'un essai d'inhibition de la liaison du [3H] ifenprodil dans le cortex cérébral de rat (Schoemaker et coll., Eur. J. Phar¬ macol . (1990) 183 1670) . Le rat mâle Sprague-Dawley de 150 à 230 g est sacrifié et le cortex cérébral est homogénéisé dans 20 volumes de tampon Tris-HCl à 50mM (pH=7,4 à 25°C) glacé, au moyen d'un appa¬ reil Ultra-Turrax™ (Ikawerk) ou Polytron™ (Kinematica) . L'homogénat est lavé deux fois par centrifugation pendant 10 minutes à 45000χg, le culot étant remis en suspension dans du tampon frais. Le culot final est repris dans 20 volumes du même tampon. Un aliquote de 100 μl de cette suspension est incubé dans un volume final de 1000 μl avec 0,5 nM de [3H] ifenprodil (acti¬ vité spécifique : 30 à 35 Ci/mmole) pendant 30 minutes à 37°C, en l'absence ou en présence de substance compétitrice. Après incubation les membranes sont récupérées par filtra¬ tion sur des filtres Whatman GF/B™ prétraités avec de la polyéthylèneimine à 0,05%, puis lavés avec deux fois 5 ml de tampon glacé.The compounds of the invention have also been the subject of a test for inhibition of the binding of [ 3 H] ifenprodil in the rat cerebral cortex (Schoemaker et al., Eur. J. Phar¬ macol. (1990 ) 183 1670). The male Sprague-Dawley rat weighing 150 to 230 g is sacrificed and the cerebral cortex is homogenized in 20 volumes of ice-cold 50 mM Tris-HCl buffer (pH = 7.4 at 25 ° C.) using an apparatus. Ultra-Turrax ™ (Ikawerk) or Polytron ™ (Kinematica). The homogenate is washed twice by centrifugation for 10 minutes at 45,000 χ g, the pellet being resuspended in fresh buffer. The final pellet is taken up in 20 volumes of the same buffer. A 100 μl aliquot of this suspension is incubated in a final volume of 1000 μl with 0.5 nM of [ 3 H] ifenprodil (specific activity: 30 to 35 Ci / mmol) for 30 minutes at 37 ° C., in the absence or presence of a competing substance. After incubation, the membranes are recovered by filtration on Whatman GF / B ™ filters pretreated with 0.05% polyethyleneimine, then washed with twice 5 ml of ice-cold buffer.
On détermine la liaison non spécifique avec de l'ifenprodil lOμM, on analyse les données selon les méthodes usuelles, et on calcule la concentration CI50, concentration qui inhibe de 50% la liaison du [3H] ifenprodil.The non-specific binding is determined with lOμM ifenprodil, the data are analyzed according to the usual methods, and the IC 50 concentration is calculated, a concentration which inhibits the binding of [ 3 H] ifenprodil by 50%.
Les CI50 des composés les plus actifs sont inférieures à 50 nM.The IC 50 values of the most active compounds are less than 50 nM.
Les résultats des essais montrent que les composés de l'in- vention ont des propriétés neuroprotectrices et des propri¬ étés neurotrophes.The results of the tests show that the compounds of the invention have neuroprotective properties and neurotrophic properties.
Ils peuvent être utilisés pour le traitement et la préven¬ tion de désordres cérébraux tels que ceux qui sont consé- cutifs, par exemple, à une attaque ischémique, un arrêt cardiaque ou respiratoire, une thrombose ou une embolie cérébrale, pour le traitement de la sénilité cérébrale, de la démence consécutive aux infarctus multiples, de la démence sénile, par exemple la maladie d'Alzheimer ou la maladie de Pick, pour le traitement de l'atrophie olivo- ponto-cérébellaire et d'autres maladies neurodégénératives telles que la chorée de Huntington, la sclérose latérale amyotrophique, pour le traitement des traumatismes crâniens ou spinaux, pour la prévention des dommages neuronaux fai- sant suite à des états convulsifs ou à la présence de tu¬ meurs dans le système nerveux, pour le traitement des alté¬ rations neurologiques dues au SIDA, pour la prévention et le traitement des rétinopathies diabétiques, de la dégénéres- cence du nerf optique et des rétinopathies associées au glaucome.They can be used for the treatment and prevention of cerebral disorders such as those which are consecutive, for example, to an ischemic attack, a cardiac or respiratory arrest, a thrombosis or a cerebral embolism, for the treatment of cerebral senility, dementia following multiple infarctions, senile dementia, for example Alzheimer's disease or Pick's disease, for the treatment of olivoponto-cerebellar atrophy and other neurodegenerative diseases such as Huntington's chorea, amyotrophic lateral sclerosis, for the treatment of cranial or spinal trauma, for the prevention of weak neuronal damage health following convulsive states or the presence of tumors in the nervous system, for the treatment of neurological alterations due to AIDS, for the prevention and treatment of diabetic retinopathies, degeneration of the optic nerve and retinopathies associated with glaucoma.
Ils peuvent être utilisés aussi pour le traitement des neuropathies périphériques, telles que les neuropathies traumatiques (section ou écrasement d'un nerf) ou isché- miques, les neuropathies métaboliques (diabète, urémie), les neuropathies infectieuses, alcooliques et médicamenteuses, les neuropathies génétiques, les affections du motoneurone telles que les amyotrophies spinales et la sclérose latérale amyotrophique.They can also be used for the treatment of peripheral neuropathies, such as traumatic neuropathies (section or crushing of a nerve) or ischemic neuropathies, metabolic neuropathies (diabetes, uremia), infectious, alcoholic and medicinal neuropathies, neuropathies genetics, motor neuron conditions such as spinal muscular atrophies and amyotrophic lateral sclerosis.
Les composés de l'invention peuvent aussi être utilisés en association avec des agents thrombolytiques tels que le rt-PA (activateur tissulaire du plasminogene recombiné, d'origine humaine) pour le traitement des infarctus céré¬ braux de type thromboenbolique, ou en association avec un composé diminuant la pression intraoculaire pour le traite¬ ment du glaucome, ou encore en association avec un agent anticancéreux, en vue de réduire les effets secondaires (neuropathies, etc) de ce dernier.The compounds of the invention can also be used in combination with thrombolytic agents such as rt-PA (tissue activator of recombinant plasminogen, of human origin) for the treatment of cerebral infarctions of the thromboenbolic type, or in combination with a compound reducing intraocular pressure for the treatment of glaucoma, or alternatively in combination with an anticancer agent, with a view to reducing the side effects (neuropathies, etc.) of the latter.
A cet effet ils peuvent être présentés sous toutes formes pharmaceutiques adaptées à l'administration entérale ou parenterale, en association avec des excipients appropriés, par exemple sous forme de comprimés, dragées, gélules, capsules, suppositoires, solutions ou suspensions buvables ou injectables, dosés pour permettre une administration journalière de 1 à 1000 mg de substance active. For this purpose they can be presented in all pharmaceutical forms suitable for enteral or parenteral administration, in combination with appropriate excipients, for example in the form of tablets, dragees, capsules, capsules, suppositories, solutions or suspensions, drinkable or injectable, dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims

Revendications claims
1. Composé, éventuellement sous forme d'isomère optique pur ou d'un mélange de tels isomères, répondant à la formule générale (I)1. Compound, optionally in the form of a pure optical isomer or of a mixture of such isomers, corresponding to the general formula (I)
Figure imgf000016_0001
dans laquelle
Figure imgf000016_0001
in which
R-L représente un atome d'hydrogène ou d'halogène ou un groupe méthyle ou méthoxy, R2 représente un un atome d'hydrogène ou un groupe méthyle, etR- L represents a hydrogen or halogen atom or a methyl or methoxy group, R 2 represents a hydrogen atom or a methyl group, and
R3 représente un atome d'hydrogène ou d'halogène, à l'état de base libre ou de sel d'addition à un acide.R 3 represents a hydrogen or halogen atom, in the form of the free base or of addition salt with an acid.
2. Procédé de préparation d'un composé selon la revendi¬ cation 1, caractérisé en ce qu'on on soumet une cétone de formule générale (II)2. Process for the preparation of a compound according to claim 1, characterized in that a ketone of general formula (II) is subjected
Figure imgf000016_0002
dans laquelle Rx et R2 sont tels que définis dans la revendi¬ cation 1, avec une 4- (phenylmethyl)pipéridine de formule générale (III)
Figure imgf000016_0002
in which R x and R 2 are as defined in claim 1, with a 4- (phenylmethyl) piperidine of general formula (III)
Figure imgf000016_0003
dans laquelle R3 est tel que défini dans la revendication 1, en présence de paraformaldéhyde et en milieu acide, et finalement on réduit la cétone de formule générale (IV)
Figure imgf000016_0003
wherein R 3 is as defined in claim 1, in the presence of paraformaldehyde and in an acid medium, and finally the ketone of general formula (IV) is reduced
Figure imgf000017_0001
Figure imgf000017_0001
par action d'un borohydrure de métal alcalin, ou bien on fait réagir une cétone bromée de formule générale (V)by the action of an alkali metal borohydride, or else a brominated ketone of general formula (V) is reacted
Figure imgf000017_0002
Figure imgf000017_0002
dans laquelle Rλ et R2 sont tels que définis dans la revendi¬ cation 1, avec une 4- (phenylmethyl)pipéridine de formule générale (III)in which R λ and R 2 are as defined in claim 1, with a 4- (phenylmethyl) piperidine of general formula (III)
Figure imgf000017_0003
dans laquelle R3 est tel que défini dans la revendication 1, et finalement on réduit la cétone de formule générale (IV)
Figure imgf000017_0003
in which R 3 is as defined in claim 1, and finally the ketone of general formula (IV) is reduced
Figure imgf000017_0004
Figure imgf000017_0004
comme indiqué ci-dessus pour la cétone de formule générale (III) . as indicated above for the ketone of general formula (III).
3. Médicament caractérisé en ce qu'il consiste en un composé selon la revendication 1.3. Medicament, characterized in that it consists of a compound according to claim 1.
4. Composition pharmaceutique caractérisée en ce qu'elle contient un composé selon la revendication 1 et un exci¬ pient. 4. Pharmaceutical composition characterized in that it contains a compound according to claim 1 and an exci¬ pient.
PCT/FR1996/001361 1995-09-08 1996-09-05 1-phenyl-3-4-[benzylpiperidinyl-1]-propanol-1 derivatives, preparation thereof and therapeutical application thereof WO1997009310A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6509355B1 (en) 1998-10-27 2003-01-21 Alcon Laboratories, Inc. Treatment of disorders of the outer retina
US8101635B2 (en) 1997-06-30 2012-01-24 Allergan, Inc. Calcium blockers to treat proliferative vitreoretinopathy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0109317A2 (en) * 1982-10-13 1984-05-23 Synthelabo Phenyl-1-piperidino-2-propanol derivatives, their preparation and medicaments containing them
EP0308328A1 (en) * 1987-09-17 1989-03-22 Sanofi (Benzyl-piperidino)-1-propanol-2 derivatives, their preparation, their use as microbicides and compositions containing them
FR2672286A1 (en) * 1991-01-31 1992-08-07 Synthelabo 1-(4-Chlorophenyl)-2-(4-phenylmethyl-1-piperidyl)ethanol derivatives, their preparation and their application in therapeutics

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0109317A2 (en) * 1982-10-13 1984-05-23 Synthelabo Phenyl-1-piperidino-2-propanol derivatives, their preparation and medicaments containing them
EP0308328A1 (en) * 1987-09-17 1989-03-22 Sanofi (Benzyl-piperidino)-1-propanol-2 derivatives, their preparation, their use as microbicides and compositions containing them
FR2672286A1 (en) * 1991-01-31 1992-08-07 Synthelabo 1-(4-Chlorophenyl)-2-(4-phenylmethyl-1-piperidyl)ethanol derivatives, their preparation and their application in therapeutics

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8101635B2 (en) 1997-06-30 2012-01-24 Allergan, Inc. Calcium blockers to treat proliferative vitreoretinopathy
US6509355B1 (en) 1998-10-27 2003-01-21 Alcon Laboratories, Inc. Treatment of disorders of the outer retina

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